A mild method for the preparation of γ-hydroxy-α,β- acetylenic esters

Article abstract of DOI:10.1002/anie.200353400

The beauty of silver has been demonstrated in the alkynylation of functionalized aldehydes and ketones. Silver acetylides of alkynyl propiolates undergo addition to carbonyl compounds in the presence of [Cp ₂ZrCl₂] and AgOTf (see scheme) in a reaction that is compatible with both base-sensitive and acid-sensitive functional groups. Tf = trifluoromethanesulfonyl.

Full text of DOI:10.1002/anie.200353400

Angewandte
Chemie
Alkynylation
isolated compound 3 as the major product. We attributed this
undesired reaction to the facile conjugate addition of the
tertiary amine to 2, followed by loss of one iPr group. These
results prompted us to develop alternative reaction conditions
under which an aldehyde would undergo condensation with 2
in the absence of a base.
A Mild Method for the Preparation of g-Hydroxy-
a,b-Acetylenic Esters**
Shatrughan P. Shahi and Kazunori Koide*
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The preparation of metal acetylides M C C R ( M= Li,
Sn, Si, B) often involves the use of a strong base. In contrast,
the silver acetylide 5[4] can be readily prepared in nearly
quantitative yield by a known mild protocol on an ~ 8-g scale,
and this solid material can be stored at ambient temperature
in a vial for many months in the dark without any precaution
to avoid moisture (Scheme 2).[5]
The alkynylation of a carbonyl compound is a powerful
reaction for forming a carbon–carbon s bond. Highly func-
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tionalized g-hydroxy-a,b-acetylenic esters RCH(OH)C C
CO2Me (A) are promising synthetic intermediates that can be
used as precursors to a variety of complex molecules.[1] Since
the procedure was reported by Midland et al.,[2] alcohols A
have mainly been prepared by the treatment of aldehydes
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with the lithium acetylide Li C C CO2Me (1). The acetylide
1 can be generated in situ by the addition of n-butyllithium to
methyl propiolate (2). Because n-butyllithium is itself a
nucleophile toward aldehydes and ketones, the amount of
base used must be controlled carefully. Furthermore, as a
result of these strongly basic conditions access to A is mostly
limited to base-stable compounds. As this widely used method
requires a stringent balance in the stoichiometry of the
reagents, one of which is moisture sensitive, it is often difficult
to obtain satisfactory results. Therefore, a milder and more
robust synthetic method with broader scope is needed for the
preparation of alcohols A.
Scheme 2. Preparation of the silver acetylide 5.
Various silver acetylides are known to react with acid
chlorides to generate alkyl 4-oxo-2-alkynoates.[6] However, in
the absence of an additive, compound 5 failed to react with 3-
nitrobenzaldehyde to afford the alcohol 6 (Table 1, entry 1).
Table 1: [Cp2ZrCl2]-promoted alkynylation.
A recent development in the enantioselective addition of
a terminal alkyne to an aldehyde, pioneered by Carreira and
co-workers, involves the in situ generation of a zinc acetylide
in the presence of a tertiary amine.[3] However, this method
did not enable us to couple acetaldehyde with 2 to form the
corresponding methyl pentynoate 4 (Scheme 1). Instead, we
Entry
M
Reagents
t [h] Yield [%][a]
1
2
3
4
Ag none
30
30
5
0
73
95
0
Ag [Cp2ZrCl2] (1.2 equiv)
Ag [Cp2ZrCl2] (1.2 equiv)+AgOTf (0.2 equiv)
H
[Cp2ZrCl2] (1.2 equiv)
30
[a] Yield of isolated product.
After screening several additives, we found that the desired
alcohol 6 was produced in 73% yield after 30 h at 238C in the
presence of [Cp2ZrCl2] (Table 1, entry 2). Although the use of
ZnBr2, [Cp2TiCl2], and ZrCl4 led to the alcohol 6 in 4, ~ 30,
and 51% yield, respectively, neither BF3·OEt2 nor Cu(OTf)2
promoted the condensation reaction. Based on these prelimi-
nary studies, this alkynylation appears to be facilitated by
zirconium reagents. Of the solvents that we employed for the
coupling reaction (CH2Cl2, THF, MeCN), the use of CH2Cl2
gave the highest yield.
Scheme 1. Reagents and conditions: Zn(OTf)2 (1.0 equiv), iPr2NEt
(1.05 equiv), (ꢁ)-N-methylephedrine (1.05 equiv), CH2Cl2, 0!238C.
Tf =trifluoromethanesulfonyl.
[*] Dr. S. P. Shahi, Prof. Dr. K. Koide
Department of Chemistry, University of Pittsburgh
219 Parkman Avenue, Pittsburgh, PA 15260 (USA)
Fax: (+1)412-624-8611
E-mail: koide@pitt.edu
Although we have not characterized any intermediates in
[**] We thank the University of Pittsburgh, the Petroleum Research Fund
of the American Chemical Society (PRF no. 38542-G1), the
American Cancer Society (Institutional Research Grant: IRG-60–
002–40), and the Competitive Medical Research Fund of the
University of Pittsburgh Medical Center for their financial support.
Dr. Fu-Tyan Lin (NMR) and Dr. Kasi Somayajula (MS) are
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the coupling reaction, we hypothesized that [Cp2(Cl)Zr C C
CO2Me] might be the reactive species.[7] The observations by
Jordan et al. and Suzuki and co-workers that silver salts
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facilitate the coupling between [Cp2(Cl)Zr R] (R = CH3 and
R = alkenyl, respectively) and an aldehyde or a ketone
prompted us to examine whether our [Cp2ZrCl2]-promoted
coupling could be further accelerated by AgOTf.[8] Thus,
AgOTf (0.2 equiv) was used together with [Cp2ZrCl2]
(1.2 equiv). This modification accelerated the coupling reac-
acknowledged for their technical assistance. We are grateful to
Professor Dennis P. Curran for his critical comments about this
manuscript and to Dr. Tadaatsu Naka for preliminary experiments.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 2525 –2527
DOI: 10.1002/anie.200353400
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
tion dramatically; the reaction was complete after
5 h (95% yield) rather than the 30 h required in
the absence of AgOTf (Table 1, entry 3). The
necessity of the silver acetylide 5 was demon-
strated by using 2 in the presence of [Cp2ZrCl2],
which did not produce the alcohol 6 (Table 1,
entry 4).
We then screened a variety of aldehydes to
test the scope of the zirconium-promoted alkyny-
lation reaction (Table 2). Both electron-deficient
and electron-rich aromatic aldehydes reacted with
5 to form the corresponding alcohols in 76–95%
yield (Table 2, entries 1–3). Cinnamaldehyde
reacted in a 1,2-addition fashion to form the
corresponding alcohol in 93% yield (Table 2,
entry 4). The reactions of aliphatic aldehydes,
including easily enolizable phenylacetaldehyde,
also afforded the corresponding alcohols in 53–
78% yield (Table 2, entries 5–8).
This method could be used to couple 5 with
the ketone 7, even in the presence of the cyclic
ketal, to afford the corresponding alcohol 8
[Eq. (1), Scheme 3]. To test 1,2-asymmetric induc-
tion in this alkynylation method, we prepared the
aldehyde 9 according to the published protocol.[9]
We chose this aldehyde because the stereoselec-
tivity in the addition of 1 is known (38% yield,
syn:anti = 4.6:1).[10] The aldehyde 9 was converted
into the alcohol 10 under our conditions in 59%
Scheme 3. Conditions: a) 5 (1.6 equiv), [Cp2ZrCl2] (1.2 equiv), AgOTf (0.2 equiv),
CH2Cl2, 238C, 2–7 h; b) 2 (1.6–2 equiv), nBuLi or LiN(TMS)2 (1.4–1.6 equiv), ꢁ788C,
1 to 30 min. Boc=tert-butoxycarbonyl, Fmoc=9-fluorenylmethoxycarbonyl,
TMS=trimethylsilyl.
yield with a syn:anti ratio of 5.5:1 [Eq. (2), Scheme 3]. This
result shows the higher efficiency and comparable degree of
1,2-asymmetric induction of our alkynylation method at room
temperature relative to a widely-used alkynylation method
with 1 at ꢁ788C. A spiroepoxide was also found to be
compatible with this Zr-promoted alkynylation. Thus, the
alcohol 12 was produced in 77% yield with a diastereomeric
ratio of 6:1 from the aldehyde 11 [Eq. (3), Scheme 3; relative
configuration not determined]. In contrast, the treatment of
11 with 1 gave the alcohol 12 in 50% yield with a
diastereomeric ratio of 1:1. The base-sensitive N-Fmoc-
protected aldehyde 13 was subjected to the same reaction
conditions [Eq. (4), Scheme 3]. The corresponding propar-
gylic alcohol 14 was isolated in 82% yield, whereas the
addition of 1 to the same aldehyde afforded the desired
alcohol in only 18% yield. The Zr-promoted alkynylation was
also effective for the preparation of the base-sensitive
compound 16 from 15 in 68% yield [Eq (5), Scheme 3]. In
contrast, the coupling of 15 with 1 generated 16 in less than
2% yield. These examples indicate that the Zr-promoted
alkynylation method can be used for substrates that can not
be prepared under conventional conditions. The results
shown in Equations (2) and (4) also demonstrate that this
reaction is compatible with the relatively acidic carbamate
protons -NHCO2R. Although the same products were formed
in all these reactions whether AgOTf was present or not, we
found that AgOTf accelerated the reactions and led to the
formation of the products in higher yields. The quantity of
AgOTf used could be reduced to 5 mol% without a decrease
in yield (data not shown).
Table 2: [Cp2ZrCl2]/AgOTf-promoted alkynylation of aldehydes.
Entry
1
RCHO
t [h]
Yield [%][a]
95
5
2
3
76
3
4
5
PhCHO
10
2.5
4
84
93
53
CH3CHO
6
1
78
7
8
3.5
4
61
78
In summary, we have developed a novel method for the
coupling of aldehydes or ketones with alkyl propiolates in the
absence of a base. Because the reagents involved in this
[a] Yield of isolated product.
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Angewandte
Chemie
coupling reaction are easier to handle than n-butyllithium and
1, these reaction conditions can be employed on a small scale
(~ 0.5 mmol) or on a 6 mmol scale without a decrease in yield.
We have also demonstrated that various functional groups are
compatible with these alkynylation conditions. Additionally,
5, [Cp2ZrCl2], and AgOTf can be stored at room temperature
without paying particular attention to the exclusion of
moisture. The synthetic use of silver acetylides has been
limited until now to only a few reaction types.[11] This study
suggests that the formation of silver acetylides of electron-
deficient alkynes is a powerful method for the conversion of
non-nucleophilic alkynes into reactive species toward alde-
hydes and ketones. Studies into the scope and limitation
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(note: the silver acetylide of the acetylenic ketone Ag-C C-
=
C( O)CH3 was found to be shock-sensitive) of these reaction
conditions with other electrophiles and nucleophiles are in
progress in our laboratory.
Received: November 25, 2003 [Z53400]
Keywords: alcohols · aldehydes · alkynylation · silver · zirconium
.
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